Alzheimer's disease (AD) most severely affects the fastest growing segment of our population: those age 80 and older. The ability to identify nondemented persons in a preclinical phase of AD will have far-reaching implications for both improved early diagnosis and use of anti-dementia pharmacologic therapies. Neuroprotective treatments will be most effective if applied at the earliest stages, which provides an important rationale for accurate preclinical detection. However, one of the remaining obstacles centers on the difficulty in identifying persons with AD before their deficits become clinically significant. Given the extent to which cognitive and brain changes associated with normal aging overlap with those of AD, the accurate detection of early AD in advanced age groups poses a number of unique challenges. We propose to conduct a five-year longitudinal study of the Very-Old (ages 80 and older) in which the combination of neuropsychological, neuroimaging, and genetic assessments will be examined, relative to the Young-Old (ages 60-79), in an effort to identify the most salient preclinical markers of AD. Our work during the previous project period has revealed important differences by age and genetic risk in the expression of cognitive and brain changes in clinical and preclinical AD. However, much remains to be done in characterizing the progression to AD in the Very-Old. Further clarification of the evolution of these brain and behavioral differences through the use of emerging neuropsychological (e.g., cognitive discrepancy measures) and functional magnetic resonance imaging (FMRI) techniques (e.g., combined arterial spin labeling/blood oxygen level dependent [ASL/BOLD] imaging) will advance our ability to understand the unique features associated with the development of AD in those at risk. Critical examination of another risk factor for AD conversion, mild cognitive impairment (MCI), will also represent a new aim for this project. Thus, the specific aims for this renewal period are (a) to determine the profile of spared and impaired cognitive processes associated with the preclinical phase of AD in the Very-Old, (b) to determine the clinical validity of a novel definitional scheme for MCI, its clinical outcomes, and whether differential rates of MCI and its various subtypes exist between Young-Old and Very-Old, (c) to use combined ASL/BOLD FMRI to measure functional changes within the medial temporal lobe (MTL) and related structures (e.g., parahippocampal gyrus, posterior cingulate) for the quantitative estimation of the cerebral metabolic rate of oxygen consumption (CMRO2) during episodic memory encoding, and (d) to integrate neuropsychological and neuroimaging methods to better determine the profile and progression of brain and behavioral changes indicative of the preclinical period of AD between the Young-Old and Very-Old. Public health relevance: Despite the many advances in neuropsychological and neuroimaging methods over the past decade, an effort focused on integrating these findings for prediction of progression to Alzheimer's disease (AD) has been lacking, particularly for our most susceptible segment of the population (i.e., those aged 80 and older). The proposed research addresses this gap and builds upon our experience in detailed neuropsychological studies along with advances with functional MRI studies of the medial temporal lobe for application to at-risk populations. With the increasing application of FMRI techniques to the study of AD, there is a growing need for quantitative measures that can more accurately reflect neural activity and its antecedent changes during the preclinical period of AD. The primary objectives of this project are to identify neuropsychological and neuroimaging changes in older adults at risk for the development of AD. Our specific aims continue the focus on our highest known risk group (i.e., those aged 80 and above) and on genetic susceptibility (e.g., apolipoprotein E). Critical examination of another risk factor for progression to AD, Mild Cognitive Impairment, will also represent a new aim for this project.